Pyrazolo[1,5-a]pyrimidine is a commonly used scaffold in medicinal chemistry and derivatives thereof are known for their potent utility as analgesics, benzodiazepine receptor antagonists, angiotensin II receptor antagonists, angiogenesis inhibitors, anti-inflammatory agents, neuropeptide Y receptor antagonists, COX2-inhibitor and corticotrophin-releasing hormone receptor type 1 antagonists and as CHK1 inhibitors (e.g. Mayo et al (Adv. Synth. Catal. 2003, 345, 620-624; Tellew et al (Bioorg. Med. Chem. Lett. 2010, 20, 7259-7264); Chen et al (Bioorg. Med. Chem. Lett. 2004, 14, 3669-3673); Labroli et al (Bioorg. Med. Chem. Lett. 2011, 21, 471-474); Griffith et al (Bioorg. Med. Chem. Lett. 2011, 21, 2641-2645); Gilligan et al, (J. Med. Chem. 2009, 52, 3073-3083); He et al. (U.S. Pat. No. 6,313,124 B1); and Wren et al. (WO 2010/086040).
The scaffold has also been described in phosphatidylinositol 4-kinase (PI4K) inhibitors. Bianco et al (PLoS Pathogens, 2012, 8(3), 1-17) and LaMarche et al (Antimicr. Agents and Chemother. 2012, 56(10), 5149-5156) have shown that PI4K is important for hepatitis C virus (HCV) replication and Yang et al (J. Biol. Chem. 2012, 287(11), 8547-8467) have shown the same for coronavirus. McLeod et al (ACS Med. Chem. Lett. 2013, 4(7), 585-589) and van der Schaar et al (Antimicrobial Agents Chemother. 2013, 57(10), 4971-4981) have shown some imidazopyrazines derivatives inhibiting PI4K that are potent antivirals towards picornavirus.
Gudmundsson et al (Bioorg. Med. Chem. Lett. 2009, 19, 5689-5692) have disclosed some 3-arylpyrazolo[1,5-a]pyrimidines with potent activity against herpesviruses.
Hwang et al (Bioorg. Med. Chem. Lett. 2012, 22, 7297-7301) have described 3-arylpyrazolo[1,5-a]pyrimidines as PI4K inhibitors that have anti-HCV effects.
Décor et al (Bioorg Med Chem Lett. 2013, 23, 3841-7) have also shown that PI4K is important for enterovirus replication. However, they have also shown that PI4K inhibitors (non 3-arylpyrazolo[1,5-a]pyrimidines) and the 3-arylpyrazolo[1,5-a]pyrimidine 3-(3,4-dimethoxyphenyl)-2,5-dimethyl-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidin-7-amine (called T-00127-HEV1) when tested in-vivo induced mortality in mice, which raised doubts on the safety of inhibiting PI4K.